Cyclosporin A in Membrane Lipids Environment: Implications for Antimalarial Activity of the Drug—The Langmuir Monolayer Studies

Abstract

Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; however, it is also active as antiparasitic (antimalarial) drug. Antimalarial mechanism of CsA action lacks a detailed understanding at molecular level. Due to a high lipophilicity of CsA, it is able to interact with lipids of cellular membrane; however, molecular targets of this drug are still unknown. To get a deeper insight into the mode of antimalarial activity of CsA, it is of utmost importance to examine its interactions with membrane components. To reach this goal, the Langmuir monolayer technique, which serves as a very useful, easy to handle and controllable model of biomembranes, has been employed. In this work, the interactions between CsA and main membrane lipids, i.e., cholesterol (Chol), 2-oleoyl-1-palmitoyl-3-phosphocholine (POPC), and sphingomyelin (SM), have been investigated. Attractive interactions are observed only for CsA mixtures with SM, while repulsive forces occur in systems containing remaining membrane lipids. Taking into consideration mutual interactions between membrane lipids (Chol–SM; Chol–POPC and SM–POPC), the behavior of CsA in model erythrocyte membrane of normal and infected cells has been analyzed. Our results prove strong affinity of CsA to SM in membrane environment. Since normal and parasitized erythrocytes differ significantly in the level of SM, this phospholipid may be considered as a molecular target for antimalarial activity of CsA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00232-015-9814-9) contains supplementary material, which is available to authorized users.

Comparative analysis of new peptide conjugates of antitubercular drug candidates—Model membrane and in vitro studies

“…The isotherm of POPC shows a gradual change with molecular area and does not present the phase transition typical for DPPC. This shape in connection with the low phase transition temperature (-2 °C) of POPC is in agreement with the previously published results [46,47]. The DPPC+DPPG mixture conversely shows the distinct states of lipid monolayer characteristic for pure DPPC.…”

Characteristics of Polypeptide/Phospholipid Monolayers on Water and the Plasma‐Activated Polyetheretherketone Support

“…The results similar to ours were obtained by Dynarowicz et al (Dynarowicz et al, 2015) for the CsA-POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) system. High and positive values of ΔG exc were observed over the entire range of CsA molar ratios.…”

“…Subsequently, the floating film was symmetrically compressed with the barriers compressing speed rate of 20 mm min −1 . At the same time, the surface pressure-area (π-A) isotherms were registered for the monolayers kept at 20 C. The chosen value of the compression speed was in the range of 5-30 mm min −1 , the use of which does not significantly affect the course of the CsA isotherm (Dynarowicz et al, 2015). On the other hand, too low speed of barriers movement could lead to loss of polypeptide molecules that escape from the interface to the subphase, or could change the molecular conformations (Fahr and Reiter, 1999).…”

Temperature-dependent interactions in the chitosan/cyclosporine A system at liquid–air interface

“…The increase in pressure collapse suggests higher monolayer stability due to the favourable Ch-CsA interactions. The collapse point reported in the literature for the CsA monolayer on water is 27 mN m -1 [31]. Accordingly, one can claim that the AA subphase affects the surface elasticity, and consequently, the collapse pressure decreases to 17.7 mN m -1 .…”